Future impact

on medical radiation protection

from radiobiological advances

Michel Bourguignon, MD, PhD

Commissioner
The French Nuclear Safety Authority (ASN)

International conference on radiation protection in medicine

Setting the scene for the next decade - BONN 6 Dec 2012
 Factors of radiosensitivity
Young age of cells

Dose rate
DDREF

Cellular type => WT Dose fractionation

Type of radiations => WR

O2 pressure
 Global hyper-radiosensitivity at low doses
A significant effect between 100 and 300 mGy

Micronuclei
Cellular survival

Joiner & Marples 2001, Thomas 2005 Slonina, 2006, 2007

• Human glial cells T98G • Human fibroblasts &

• X Rays 240 kV keratinocytes
• Gamma Rays
 New investigation techniques
Immunofluorescence
Demonstration of DNA
double strand breaks
with fluorescent
antibodies anti-
histones g-H2AX :
– increase sensitivity by a
factor 100
– threshold : 1 mGy
– the effects of one single
Xray examination can
be seen !
Visualization of radiation induced
(Rothkamm & Löbrich 2003) DNA DSBs by foci g-H2AX (green) of
non transformed human fibroblasts
 Individual radiosensitivity

• Known in radiotherapy for high doses (side

effects & complications)
• Due to abnormal DNA lesion signalisation and
repair
• Recently demonstrated for low doses
• ≈ 5-15% of the population
• Significant effect (range 1 to 10)
 Individual radiosensitivity at 2 Gy
Characterization of 40 lines of skin fibroblasts of
syndroms of known radiosensitivities (N.Foray)

% cell survival at 2 Gy Immunofluorescence

100
3 specific Antibodies
 g-H2AX :
% de survie à 2Gy

80 Groupe I recognition and accurate repair by

g-H2AX is an joining
60 inverse indicator  ATM :
of survival at
signalization (from cytoplasm to
Groupe II 24h
40 nucleus)
 MRE11 :
20 Groupe IIIa poor DNA DSB repair & genomic
Groupe IIIb instability
0
0 10 20 30 40 50 3 groups of radiosensitivity
% de Cassures double-brin
% unrepaired DNAnon réparées
DSBs and genomic instability
 Study on human mammary Individual radiosensitivity
epithelium exposed ex vivo
to ionizing radiations in the at low doses
conditions of mammography
Induction of DNA-DSB
(Colin 2011)
between 10 min & 24 h
Spontaneous 10 min 24 h
100%
90%
g-H2AX
80%
percentage of cells

foci
70%
≥15
60%
1-14
50%
no
40%
30%
20%
10%
0%
0 2 4 2+2 2 4 2+2 mGy
mG

Dose effect & Repetition of doses effect

 Patients with low risk of
cancer / high familial risk
Individual radiosensitivity
(C.Colin 2011) at low doses

3 effects increased in HR patients p < 0,001

10 min 24 h 10 min 24 h
100% 100%
90% 90%
80% 80%
percentage of cells

percentage of cells
foci foci
70% 70%
≥15 ≥15
60% 60%
1-14 1-14
50% 50%
no no
40% 40%
30% 30%
20% 20%
10% 10%
0% 0%
0 2 4 2+2 2 4 2+2 mG 0 2 4 2+2 2 4 2+2 mG
a.

Low risk patients High Risk patients

 Radiobiological advances
paving the way for the next decade (1)

• Global hypersensitivity to low doses of

medical imaging to be further explored
– Immunofluorescence techniques
– Effects of 30 kV mammography / 120 kV CT
– Impact of dose rate
– Effects of iodinated contrast agents
– Global hypersensitivity and bystander effect
– Comprehension of pathways : DNA-PK…
 Radiobiological advances
paving the way for the next decade (2)
• Individual radiosensitivity to low doses of
medical imaging to be further explored
– Signaling & repair pathways of DNA lesions :
immunofluorescence, other techniques …
– Lymphocyte CD4/CD8 apoptosis
– Other biomarkers : cytogenetic, polymorphism… ?
– Impact of repetition of exposure after short interval
(second view)
– % population : 5-15 % ? … 20 %
– Transfer from research laboratory to routine
testing
 Radiobiological advances
paving the way for the next decade (3)

• Individual radiosensitivity / oncogenesis

– DNA injuries : physicochemical process
– DNA lesions result from poor signalization and
repair of injuries
– DNA lesions do not mean cancer but cancers
result from poor combinations of DNA lesions
(how many?)
– Individual radiosensitivity and oncogenesis have
many mechanisms in common (but do not
superimpose completely) : studying one =
studying the other
 Radiobiological advances
paving the way for the next decade (4)
• Need to focus on key issues in the
context of increase medical doses
– Most sensitive patients : children, family risk of
cancer patients, hyper-radiosensitive patients, …
– Most sensitive tissues : breast, thyroid…
– Most dosing examinations : CT (neck, chest,
abdomen & pelvis)
– Most frequent examinations : CT, mammography
– Subgroup of patients with repetition of
examinations (screening) and good life
expectancy : women (breast), cardiac patients,
backbone problems
 Radiobiological advances
paving the way for the next decade (5)
• Probable need to review the Radiation
Protection system
– So far the RP system takes into account sensitivity
factors : age, WR, WT, O2, fractionation, DDREF
– Need to include ASAP individual radiosensitivity
as a factor : WS and global sensitivity to low doses
– Justification and optimization remain as
milestones because the risk of medical exposure
is very low but is (much) greater in radiosensitive
patients and in patients with repeated exposures
in whom epidemiology may become
demonstrative !